The major objective of the proposed studies is to determine the mechanisms by which glucocorticoids control metabolic processes in the liver. In particular, we wish to study and compare the mechanisms by which glucocorticoids exert their direct and permissive effects on the liver. A major goal of the proposed studies is to determine if the so-called permissive effects of steroids are produced by the same mechanism as the direct effects of steroids. Since it is thought that specific liver glucocorticoid receptors are involved in mediating the direct effects of steroids on hepatic metabolism, a large portion of the proposed studies will be devoted to elucidating the role these receptors play in mediating the permissive effects of the glucocorticoids. The permissive effect we will study is glucagon stimulated hepatic gluconeogenesis which requires adrenal steroids, i.e., the steroids "permit" the action of glucagon. The direct effects we propose to study will involve the alterations in hepatic lipid metabolism produced by dexamethasone. The proposed experiments are thus designed to answer the following specific questions. Are the direct and permissive effects of steroids produced by the same mechanism? Does this mechanism involve specific cytoplasmic and nuclear receptor proteins for glucocorticoids? Is de novo protein synthesis required for the direct and permissive effects of steroids? The successful completion of the proposed studies should lead to an increased understanding of the relationships between the direct and permissive effects of steroids not only in the liver, but also in other systems.